A significant fraction of patients with Alzheimer's Disease (AD) also have acquired hearing loss. Why these two diseases of the aged are correlated is a matter of great debate. In some cases, both may arise from the same cause. In that case, acquired hearing loss might become a useful biomarker for early treatment of AD. Alternatively, untreated hearing loss might drive AD progression, either through increasing social isolation or by exacerbating working memory deficits during communication. In the latter case, treating hearing loss could delay the onset or progression of AD. Unfortunately, hearing aid use is not widespread among people with acquired hearing loss, prompting interest in biological cures. This parent R01 grant investigates ERBB2 signaling as a candidate for stimulating inner ear regeneration, using transgenic mouse models to over-express an constitutively active form of ERBB2 (CA- ERBB2) in supporting cells of the inner ear. We have recently published that activation of ERBB2 in the newborn mouse cochlear drives the production of ectopic hair cells. We also show preliminary data indicating that young adult mice with CA-ERBB2 significantly recover low-frequency hearing after traumatic noise exposure, compared to their control siblings. While still quite preliminary, this exciting result may also be useful in studies of the interaction of AD and acquired hearing loss. We seek supplemental funding to expand our ongoing experiments, so that we might address new basic questions about AD in the context of this new hearing restoration. We plan to employ mice harboring two transgenes, the K670N and M671L mutations in the amyloid precursor protein (APP), and the M146L mutation in presenilin 1 (PS1). We will cross such APP/PS1de9 mice into our current transgenic system, where we obtain mice that can express CA-ERBB2 under control of a Tet-ON promoter regulated by a supporting cell specific CRE recombinase, Fgfr3-iCRE and ROSA-rtTA. We will then investigate whether mice with both CA- ERBB2 and APP/PS1de9 exhibit similar recovery dynamics from damage as those with CA-ERBB2 alone. We have the advantage that we can design follow-up experiments regardless of the outcome. If AD-related transgenes prevent hearing loss recovery, then we will plan to investigate a causative role for these genes in hearing loss. If AD-related transgenes do not prevent hearing recovery, then we plan to investigate if this intervention can delay onset or progression of AD-like symptoms in mice. Thus, we predict that these experiments will further a greater understanding into this puzzling dynamic of hearing loss and AD progression.